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Kidney International, Vol. 63, Supplement 85 (2003), pp. S91–S96

Calcimimetic agents: Review and perspectives

PABLO UREN˜ A and JOA˜ O M. FRAZA˜ O

Service de Ne´phrologie et Dialyse, Clinique de l’Orangerie, Aubervilliers, France; and Department of Nephrology, Hospital Sa˜o Joa˜o, Porto, Portugal School of Medicine, University of Porto, Portugal

Calcimimetic agents: Review and perspectives. tal surgical parathyroidectomy every year as a result of Background. Recognition of the role of the extracellular treatment failure or severe clinical complications [4]. calcium-sensing receptor (CaR) in mineral metabolism has Parathyroid surgery is associated with major risks related greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracel- to anesthesia, pre- and post-surgical complications, in- 2ϩ lular ionized calcium (ec(Ca )) regulates PTH, calcitonin secre- duction of permanent hypoparathyroidism, or recur- tion, urinary calcium excretion, and, ultimately, bone turnover. rence of the secondary . The hypo- Methods. The cloning of the CaR and the discovery of muta- parathyroid state is associated with low bone remodeling, tions that make the receptor less or more sensitive to calcium have allowed a better understanding of several hereditary dis- adynamic bone disease, increased serum calcium and orders characterized by either hyperparathyroidism or hypo- phosphorus product, vascular calcifications, and the dev- parathyroidism. The CaR, able to amplify the sensitivity of the astating lesions of calciphylaxis [5–7]. Thus, the ideal CaR to Caϩϩ and suppress PTH levels with a resulting decrease ϩϩ treatment would be a drug that could efficiently, safely, in blood Ca , became an ideal target for the development of and cyclically suppress the secretion of parathyroid hor- compounds, the calcimimetics. Experience with the calcimi- metic R-568 in patients with primary and secondary hyperpara- mone (PTH) without interfering with the calcium and thyroidism and parathyroid carcinoma are summarized. phosphorus intestinal absorption. Results. The first clinical studies with the first-generation calcimimetic agents have demonstrated their efficacy in low- Parathyroid cell calcium-sensing receptor ering plasma intact PTH concentration in uremic patients with During the last 25 years, scientists have been interested secondary hyperparathyroidism. However, the low bioavail- ability of these first calcimimetics predicts a difficult clinical in demonstrating that the secretion of PTH is mainly utilization. The second-generation calcimimetic, AMG 073, regulated by a membrane receptor on the parathyroid having a better pharmacokinetic profile, appears to be effective cells which is capable of responding to small variations and safe for the treatment of secondary hyperparathyroidism, in the extracellular ionized calcium ( (Ca2ϩ)) concentra- suppressing PTH levels while simultaneously reducing serum ec phosphorus levels and the calcium x phosphorus product. tion. It was only in 1993 that Brown et al [8] cloned the Conclusion. The advantage of controlling PTH secretion parathyroid cell calcium-sensing receptor (CaR). This is without the complications related to hypercalcemia, hyper- a 121-kD protein with three main structural domains, a phosphatemia, and increased calcium x phosphorus product is long extracellular N-terminal domain, seven membrane- very promising. spanning helices, and a hydrophobic intracellular C-ter- minus characteristic of G-protein coupled receptors. The CaR belongs to the type III family of structurally unique More than a century after its identification, secondary G protein-coupled receptors, which includes other CaRs, hyperparathyroidism remains a problem in more than metabotropic glutamate receptors (mGluR1-8), putative one third of patients with chronic renal insufficiency pheromone receptors expressed in the rodent vomerona- [1–3]. Despite the use of new vitamin D analogs and new sal organ (V2Rs), three sweet taste receptors (T1R1-3), calcium-free, aluminum-free phosphate binders, many and GABAB receptors [9]. The parathyroid and kidney patients with secondary hyperparathyroidism are not CaRs are 1081 and 1079 amino acid long proteins, respec- controlled due to vitamin D–associated hypercalcemia tively. The CaR can be considered a low-affinity receptor, and hyperphosphatemia, or parathyroid gland resistance. 2ϩ responding to relatively high concentration of ec(Ca ), Three percent to 5% of patients require a total or subto- over one mmol/L. The limited selectivity of the receptor is responsible for its activation by numerous divalent or trivalent cations in addition to calcium, such as magne- Key words: calcium-sensing receptor, calcimimetics, secondary hyper- parathyroidism, , , renal osteodys- sium, gadolinium, aluminum, and lanthanum, and by trophy, review. other polycationic compounds such as neomycin, sper-  2003 by the International Society of Nephrology mine, and numerous amino acids [10, 11]. The activation

S-91 S-92 Uren˜a and Fraza˜o: Calcimimetic agents of the CaR by any one of these agonists results in the Table 1. Agonists and antagonists of the calcium receptors stimulation of the Gi protein, phospholipase C, inositide Agonists trisphosphate cascade, the mobilization of intracellular Type I calcimimetics Positive charges EC50 calcium, and the activation of protein kinase C (PKC). Inorganic cations Its activation also inhibits the adenylcyclase signaling Calcium 2 1.2 mmol Magnesium 2 5.2 mmol pathway and protein kinase A (PKA) [8, 12]. Modifica- Lanthanum 3 33 ␮m tions in these signal transduction pathways result in the Gadolinium 3 20 ␮m inhibition of PTH secretion. Aluminum 3 4 mmol Barium 2 — The physiologic relevance of the cloned CaR in de- Cadmium 2 — 2ϩ termining the level at which circulating ecCa is set has Nickel 2 — been established by the identification of several inherited Cobalt 2 — Iron 2 — diseases due to inactivation or activation mutations in Lead 2 0.1 mmol the parathyroid CaR gene, namely familial hypocalciuric Polyamines hypercalcemia, neonatal severe hyperparathyroidism, Spermine 3 150 ␮m Spermidine 4 2.0 mmol and familial hypercalciuric hypocalcemia [12–14]. Pentaethylenehexamine 6 500 ␮m Hexacyclin 6 21 ␮m Calcimimetic agents Aminosides Streptomycin 3 600 ␮m After discovery of the CaR there was interest in the Bekanamycin 5 200 ␮m development of compounds with the capacity of modu- Gentamycin 5 150 ␮m lating the function of the receptor, thus providing an- Neomycin 6 30 ␮m Polybasic amino acids and other tool for the medical treatment of both primary other peptides and secondary hyperparathyroidism (Table 1) [10, 15– Protamine 21 75 ␮m 17]. The first compounds were called “type I calcimimet- Polylysine (38 kD) 55 3 nmol 2ϩ Polyarginine (100 kD) 640 4 nmol ics” because they mimicked the effects of ecCa . The Type II calcimimetics second compounds were called “type II calcimimetics” NPS R-467 1 4.8 ␮m because they changed the structural conformation of the NPS S-467 1 70 ␮m NPS R-568 1 0.6 ␮m CaR and stereo-selectively increased its sensitivity to NPS S-568 1 9.8 ␮m 2ϩ ecCa . Type II calcimimetics lose their effect in the ab- AMG 073 — 2.8 ␮m 2ϩ KRN568 — (Cmax) 6.5 ng/mL sence of ecCa and do not really mimic the effect of 2ϩ Others ecCa ; therefore, naming them calcimimetics is probably Thimerosal (merthiolate) — — inappropriate and they should be called “positive allo- Antagonists steric modulators of CaR.” The third compounds have Calcilytics NPS 2143 — — been called “calcilytics” because they inhibit CaR func- tion and stimulate PTH secretion [10, 17]. It has been suggested by site-directed mutagenesis studies that the mode of action of the type II calcimimetics agents may cemia might be due to the abolition of PTH secretion reside in its binding to the seventh transmembrane do- main of the CaR [18]. Several calcimimetic agents have with a decrease in bone turnover, and not to the stimula- already been developed: first-generation compounds, in- tion of the renal CaR [19, 20]. cluding NPS R-567, NPS S-567, NPS R-568, NPS S-568, Six heterogeneous studies in uremic animals with sec- and KRN-568, and a second-generation compound, AMG ondary hyperparathyroidism have been published (Table 073. 2). In these studies, NPS R-568 at doses ranging from 1.5 to 15 mg/kg/day reduced the proliferation rate of Action of calcimimetic agents in vitro and in animals parathyroid cells by 50%, stopped the progression of The calcimimetic agents suppress the secretion of PTH parathyroid gland hyperplasia, and corrected the histo- in a dose-dependent manner in cultured parathyroid cells logic signs of high bone turnover [19, 21–25]. and in healthy animals. In animals, oral NPS R-568 pro- Clinical use of calcimimetic agents vokes a rapid dose-dependent (ED50, 1.1 Ϯ 0.7 mg/kg) decrease in serum PTH and calcium concentrations. At Calcimimetic agents have been tested in subjects with a dose of 3.3 mg/kg, the maximum effect on PTH levels normal renal function [26, 27]. In one study, 18 post- is reached 15 minutes after administration. At doses menopausal women were randomized into two groups; ranging from 10 to 100 mg/kg, hypocalcemia is almost one group received increasing doses of oral NPS R-568 immediate, lasting for more than 24 hours. Studies per- (10 to 400 mg/day), and the other group was treated with formed in rats submitted to bilateral nephrectomy and placebo. The levels of intact PTH decreased by 34% parathyroidectomy suggest that the striking hypocal- from baseline values 30 to 120 minutes after the dose of Uren˜a and Fraza˜o: Calcimimetic agents S-93

Table 2. Calcimimetics in animals with uremic secondary hyperparathyroidism Duration Reference Type of CRF Dose of calcimimetic of treatment Main results Wada et al [21] Nx. 5/6th 1.5–15 mg/kg/b.i.d. (gavage) 4 days 50% reduction in the proliferation rate of parathyroid cells Fox et al [19] Nx. 5/6th 5–10 mg/kg/q.i.d. (gavage) 6 hours 82 to 94% reduction in serum PTH levels Wada et al [22] Renal arterial 30–100 ␮mol/kg/q.i.d. (gavage) 54 days 50% reduction in serum PTH levels ligation 20 ␮mol/kg/q.i.d. (subcutaneous) 54 days Normalization of serum PTH levels Chin et al [23] Nx. 5/6th 10–30 ␮mol/kg/q.i.d. (gavage) 8 weeks Stop the progression of secondary hyperparathyroidism 20 ␮mol/kg/q.i.d. (subcutaneous) Wada et al [24] Nx. 5/6th 3–30 mg/kg/q.i.d. (gavage) 30 days Correction of histologic signs of secondary hyperparathyroidism Ischii et al [25] Adriamycin 10 mg/kg/q.i.d. (gavage) 8 weeks Restoration of trabecular bone volume; 14% increase in bone mineral density Renal arterial 4.5 mg/kg/q.i.d. (subcutaneous) 8 weeks No bone effect ligation Nx. is nephrectomy.

10 mg, and decreased by 74% after 400 mg of NPS R-568. PTH levels from 2000 to 3500 pg/mL. This PTH increase The duration of PTH suppression was also dose-depen- was believed to occur due to progression of the parathy- dent and lasted approximately 12 hours. Serum PTH roid carcinoma. The patient remained very active, trav- levels decreased even in the presence of a steady decline eled extensively, and had no side effects over a follow- in plasma calcium concentration [27]. up of more than 600 days. In addition, all measures The NPS R-568 was also tested in patients with pri- of cardiac, renal, hepatic, hematologic, and pancreatic mary hyperparathyroidism. Twenty postmenopausal function remained stable throughout the period of treat- women were enrolled and randomized into two groups; ment. Although such observations were made only in one group received a unique dose of NPS R-568 (from one patient, the data showed that R-568 could be given 4 to 160 mg), and the other group received a placebo safely over a prolonged period of time. [28]. The minimal effective dose of NPS R-568 was 20 Two complete reports were published regarding the mg, resulting in a 26% suppression of the intact PTH use of NPS R-568 in dialysis patients with secondary levels. With doses of 80 and 160 mg, serum PTH fell by hyperparathyroidism. The first study [30] was a small, 42% and 51%, respectively. The lowest serum intact two-day study in seven patients with mild hyperparathy- PTH levels were observed two hours after the adminis- roidism. Doses of 40 or 80 mg caused PTH levels to fall tration of either 80 or 160 mg of NPS R-568, and they by more than 30% after the first dose in 5 of 7 patients, returned to the initial baseline values four and eight and more than 60% after the second dose in 6 of 7 hours after the administration of 80 and 160 mg, respec- patients. With doses of 120 and 200 mg, PTH was reduced tively. Serum ionized calcium decreased slightly from by more than 60% after the first dose in 6 of 7 patients. 1.35 to 1.30 mmol/L four hours after the dose of 160 mg. After 24 hours, the pretreatment PTH level was still Similarly, the urinary excretion of calcium increased by 50% lower than the initial basal value; nonetheless, PTH a factor of 2.3 only two hours after the administration fell 50% or more after the second dose in 6 of 7 patients. of 160 mg of NPS R-568 and returned to baseline values Blood Caϩϩ was not significantly changed after the low eight hours later. dose, but fell significantly after the high dose. Serum The calcimimetic agent, R-568, was given to a patient calcitonin levels doubled four hours after the high doses with inoperable parathyroid carcinoma who presented and returned to baseline 48 hours later. The second study with hypercalcemia (blood Caϩϩ 1.96 mmol/L), high [16] was performed in 21 hemodialysis patients with mod- PTH levels (1128 pg/mL), and altered mental status; erate secondary hyperparathyroidism (PTH between 300 hypercalcemia failed to respond to intravenous saline and 1200 pg/mL). They were randomized into two groups: and furosemide, several doses of intravenous pamidro- 5 patients received a placebo and 16 patients received nate, and salmon calcitonin over 18 days [29]. The calci- an oral dose of 100 mg per day of NPS R-568 for 15 mimetic was initiated at 200 mg/day and subsequently days. In the treated group, the serum level of PTH fell increased to 400 mg/day. The patient’s symptoms im- by 66%, 78%, and 70% after one, two, and four hours, proved after three days of R-568 treatment and the pa- respectively, and remained significantly lower than the tient was discharged home after 28 days of treatment basal values during the next 24 hours. Despite lower with a blood Caϩϩ of 1.53 mmol/L and a PTH level of ionized calcium concentrations, predose intact PTH lev- 357 pg/mL. Treatment with the calcimimetic was contin- els decreased progressively over the first nine days of ued and the dose was titrated up to 600 mg/day; this treatment with R-568. Levels remained below pretreat- treatment maintained the total serum calcium between ment levels for the duration of the study, in contrast 2.75 to 3.0 mmol/L, despite the progressive increase in with the placebo treated group. Serum total and blood S-94 Uren˜a and Fraza˜o: Calcimimetic agents ionized calcium levels decreased from pretreatment lev- was 625 Ϯ 310 pg/mL (mean Ϯ SE) for the 36 patients els in patients given R-568, whereas values were un- treated with AMG 073 and 582 Ϯ 421 pg/mL for the changed in those given a placebo. Blood ionized calcium placebo-treated patients. The intact PTH levels de- levels fell below 1.0 mmol/L in seven of 16 patients re- creased by 32.5% from the baseline during the mainte- ceiving R-568; five patients withdrew from the study nance phase in the AMG 073 group and increased by after developing symptoms of hypocalcemia, while three 3.0% in the placebo-treated patients. In the AMG 073 patients completed treatment after the R-568 dose was group the calcium x phosphorus product at the end of reduced. An interesting point of this study is the pharma- the maintenance period was decreased by 7.9% from the cokinetic data of NPS R-568. After a single dose, its baseline value, compared to an increase of 11.0% in the maximal plasma concentration was obtained after a vari- placebo-treated group. The serum phosphorus was also able lapse of time, ranging from 1 to 24 hours. The peak reduced by 2.6% in the AMG 073 treated patients and plasma concentration, often observed between 2.5 and the mean serum calcium level was reduced by 4.6% from 4.4 hours, greatly differed from one patient to another baseline, although the absolute serum calcium level re- (from 0.42 to 42.2 ng/mL). The bioavailability of NPS mained within the normal range. Ͻ R-568 appears to be very low ( 1%), which suggests The potential of the second-generation calcimimetic that manipulation of this first-generation calcimimetic for treatment of secondary hyperparathyroidism in he- would be difficult. modialysis patients has been shown in the combined Due to the pharmacokinetic profile and interactions results of three, 12-week, randomized, double-blind, pla- with other drugs, the development of R-568 was discon- cebo-controlled, dose titration trials (abstract; Drueke tinued and a second-generation calcimimetic agent, AMG et al, J Am Soc Nephrol 12:764A, 2001). Two hundred 073, developed. In the initial clinical trials, AMG 073 and fifteen hemodialysis patients (141 AMG 073 treated showed the potential to treat hemodialysis patients with and 74 placebo treated) with serum intact PTH levels secondary hyperparathyroidism with promising results. Ն300 pg/mL, calcium levels between 8.8 mg/dL and 11.0 A randomized, double-blind, placebo-controlled, multi- mg/dL, and a calcium x phosphorus product less than center study was conducted in hemodialysis patients with 70, were evaluated. AMG-073 was titrated up to 50 mg/ secondary hyperparathyroidism and six sequential single day in two studies, and 100 mg/day in one study, based doses were administered (5, 10, 25, 50, 75, and 100 mg upon PTH levels and safety profile. Mean serum PTH of AMG 073 or placebo) [31]. Doses of 25, 50, 75, and levels was reduced by 20% to 33% in the AMG 073 group 100 mg caused a dose-dependent decrease in plasma intact PTH with a maximum suppression observed be- and increased by 16% in the placebo group. Eighty-three tween two and four hours after administration, followed percent of AMG 073 patients had a reduction in serum by a slow recovery of the intact PTH during the subse- PTH levels of more than 30% at the end of 12 weeks. quent hours but remaining below the baseline values Mean serum calcium x phosphorus product decreased after 24 hours. Single doses of 75 and 100 mg of AMG 073 by 8% in the AMG 073 group and increased by 14% in reduced serum calcium by 8.3% and 9.4%, respectively. the placebo group. No major side effects were reported. Following these results daily, fixed doses of 10, 25, and 50 Another randomized, placebo-controlled, double-blind, mg of AMG 073 were administered for eight consecutive 12-week trial evaluated AMG 073 at doses up to 180 mg days in hemodialysis patients with plasma intact iPTH in 82 hemodialysis patients (abstract; Block et al, JAm Ն250 pg/mL and Յ1500 pg/mL [31]. Doses of 25 and 50 Soc Nephrol 13:572A, 2002). These patients had PTH mg were associated with decreases in iPTH concentra- levels Ն300 pg/mL, despite standard therapy with phos- tions. The 50 mg dose was associated with a decrease in phate binders and vitamin D. The mean PTH levels de- mean serum calcium levels. On day eight, serum phos- creased by 47% from baseline in the active drug group, phorus levels and the calcium x phosphorus product were and the target PTH level was achieved in 54% of the reduced from baseline levels in all treatment groups re- patients not controlled on current therapy. Percent of ceiving AMG 073. reductions in calcium and phosphorus product in patients The efficacy and safety of AMG 073 was shown in receiving AMG 073 were of similar magnitude to that a double-blind, placebo-controlled, 18-week study with observed in previous studies. The incidence of adverse dose titration during the first 12 weeks using daily doses events was similar in the two treatment groups. of 10, 20, 30, 40, and 50 mg AMG 073 or placebo (ab- stract; Lindberg et al, J Am Soc Nephrol 11:578A, 2000). Because of the good safety profile observed in the previ- CONCLUSION ous study, doses of AMG 073 were titrated up to 100 After the cloning of the CaR and the development mg per day in another study (abstract; Quarles et al, JAm of positive allosteric modulators of CaR, the medical Soc Nephrol 12:773A, 2001). Seventy-one hemodialysis treatment of several hyperfunctioning and/or hypofunc- patients were evaluated. The baseline intact PTH value tioning parathyroid glands states seems to be devoted Uren˜a and Fraza˜o: Calcimimetic agents S-95

Table 3. Potential medical uses of calcium receptor modulators may be very useful for the treatment of primary and Parathyroids secondary hyperparathyroidism, parathyroid carcinoma, Inherited parathyroid disorders and probably a few other rare disorders, such as para- Primary hyperparathyroidism Secondary hyperparathyroidism thyromatosis and calciphylaxis. Parathyroid carcinomatosis ´ Surgical parathyroidectomy failure Reprint requests to Dr. Pablo Uren˜a, Service de Nephrologie et Dia- Ectopic parathyroid gland localization lyse, Clinique de l’Orangerie, 11 boulevard Anatole France, 93300 Aub- Parathyromatosis ervilliers, France. Parathyroid surgery refusal E-mail: [email protected] Surgical contraindications Cardiovascular REFERENCES Arterial hypertension Calciphylaxis 1. Hruska K: New concepts in . Nephrol Dial Renal Transplant 13:2755–2760, 1998 Diuretic 2. 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